PROJECT SUMMARY The defining characteristic of addiction is an uncontrollable urge to use drugs despite negative conse- quences (i.e., punishment). Addicted individuals find it difficult to curb drug-seeking behaviors even when they lead to harmful consequences, indicating that these behaviors are resistant to punishment. A similar type of punishment resistance has been observed in recent animal models of addiction, with a subset of rats continuing to self-administer cocaine despite receiving footshock. A prevailing view in the field is that punishment resistance arises from failure to exert goal-directed control over habits. However, a major gap in this account is that there is a lack of empirical evidence to support it. While goal-directed and habitual behaviors are known to be mediated by separate neural systems in dorsomedial striatum and dorsolateral striatum, respectively, much less is known about how punishment affects well-established behavior guided by these systems. Without a clear understanding of what drives punishment resistance in addiction, development of successful treatment strategies will continue to be hindered. The overall objective of this project is to establish a link between habitual responding and pun- ishment resistance in a rat self-administration model. The central hypothesis is that punishment resistance stems from a failure to switch from habitual responding to goal-directed control, due to reduced recruitment of cortical and thalamic inputs to dorsomedial striatum. The specific aims of this project are to: determine the role of habitual responding in punishment resistance, identify striatal components involved in punishment resistance and sensi- tivity, and identify inputs to striatum that mediate the response to punishment. These aims will be investigated using a systems-level approach that involves translationally-relevant animal models of addiction, optogenetic tools, and a novel outcome devaluation procedure that was developed to assess habitual responding for cocaine. These studies will provide critical new evidence for the theoretical framework commonly used by the field, and provide key insights into the behavioral processes and neurobiological mechanisms of compulsive drug use despite negative consequences.